Overexpression of tumor necrosis factor (TNF)α and TNFα receptor I in human viral myocarditis: clinicopathologic correlations

Abstract

Proinflammatory cytokines, including tumor necrosis factor (TNF)a, have been recognized as important physiopathogenetic factors in the initiation and continuation of inflammatory cardiomyopathies. Experimental and preliminary human studies have demonstrated that TNFa plays a crucial role in enteroviral-induced myocarditis. In this study, we investigated the expression of TNFa and both its receptors (TNFRI and TNFRII) in both viral and nonviral myocarditis. Myocardial expression of TNFa was then correlated with different clinical and pathologic findings. TNFa expression was investigated in endomyocardial biopsies obtained from 38 patients with myocarditis and from eight control subjects by using reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry. Viral etiology was diagnosed by PCR in 20 cases: enterovirus in seven, Epstein-Barr virus in four, hepatitis C virus in three, adenovirus in two, influenza virus in two, cytomegalovirus in one, and double infection adenovirus and enterovirus in one. Immunohistochemistry was also used to analyze both TNFa receptors (RI and RII). A semiquantitative analysis was employed (score 0-3) for necrosis, inflammation, fibrosis and immunohistochemical findings. TNFa mRNA and TNFa protein were significantly more present in viral myocarditis than in nonviral myocarditis (16/20 vs 3/18, P ¼ 0.001). Remarkable immunostaining was observed for both receptors, particularly TNFRI. Histological analysis revealed that myocardial necrosis (mean score 1.89 vs 1.15, P ¼ 0.01) and cellular infiltration (mean score 2.26 vs 1.78, P ¼ 0.05) were more prominent in TNFa-positive cases. Among TNFa-positive cases, the greater TNFa mRNAs, the more impaired was cardiac function. Our findings suggest that the expression of TNFa may play an important role in the pathogenesis of viral myocarditis of any etiology and may influence the severity of cardiac dysfunction. Cytokine effects are more strictly linked to overexpression of TNFRI.

Role of the Cholinergic Antiinflammatory Pathway in Murine Autoimmune Myocarditis

“…For example, patients with infectious and viral myocarditis have elevated levels of TNF-␣ protein and mRNA in myocardial tissue. [32][33][34] TNF-␣ plays a major role in the progression of myocarditis, given that targeted myocardial overexpression of TNF-␣ leads to severe myocarditis, cardiomegaly, and progressive myocardial fibrosis. [35][36][37] In addition, exogenously administered TNF-␣ increases myocarditis, and inhibition of TNF-␣ with antibodies or soluble receptors attenuates viral myocarditis.…”

Myocarditis

“…25,28 The causative relationship between HCV infection and dilated cardiomyopathy remains ambiguous; increased tumor necrosis factor (TNF) and cytokine expression have been implicated. 29 Bowles et al 24 conducted a multicenter study of 624 patients with biopsy-proven myocarditis (66%) or borderline myocarditis (34%). Evidence of viral genome (adenovirus, enterovirus, and cytomegalovirus in decreasing frequency) was identified in 239 (38%) of subjects' endomyocardial biopsies.…”

The Key Players of Coxsackievirus-Induced Myocarditis

“…Importantly, cardiac myocytes express TNF receptors TNFR1 (TNFRp55) and TNFR2 (TNFRp75), implicating the possible importance of enhance TNF-in the myocardium. Histological analysis revealed that myocardial necrosis and cellular infiltration are more prominent in TNF--positive cases further supporting the notion that the expression of TNF-significantly contributes to the pathogenesis of viral myocarditis and including the severity of cardiac dysfunction (Calabrese et al 2004). Chemokines act as chemotactic mediators in leukocyte trafficking to sites of infection (Groom et al 2011).…”